Cisplatin interaction with cysteine and methionine in aqueous solution: computational DFT/PCM study

Area of Science:

• Computational Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Cisplatin is a crucial platinum-based chemotherapy drug.
• Understanding cisplatin's interactions with biomolecules is key to optimizing its efficacy and reducing toxicity.
• Sulfur-containing amino acids like cysteine and methionine are potential binding sites for platinum drugs.

Purpose of the Study:

• To investigate the binding preferences of cisplatin with sulfur-containing amino acids using computational modeling.
• To elucidate the reaction mechanisms and thermodynamic stability of cisplatin-amino acid complexes.
• To compare solution-phase interactions with gas-phase behavior.

Main Methods:

• Utilized a polarizable continuum model (PCM) for simulating interactions in solution.
• Employed density functional theory (DFT) calculations, specifically B3LYP functional with various basis sets (6-31+G(d), 6-311++G(2df,2pd)).
• Analyzed two cisplatin complexes: chloro (cis-[Pt(NH3)2Cl(H2O)]+) and hydroxo (cis-[Pt(NH3)2(OH)(H2O)]+).

Main Results:

• Cysteine's sulfur atom showed the highest thermodynamic preference for binding to cisplatin.
• Methionine's binding preference shifted from nitrogen (in the chloro complex) to sulfur (in the hydroxo complex).
• The most stable structures in solution were found to be kappa2(S,N) chelates, consistent with experimental observations, with methionine also showing stability in kappa2(N,O) chelates.

Conclusions:

• Cisplatin exhibits a strong preference for binding to cysteine sulfur in aqueous solution.
• The coordination environment of cisplatin influences methionine's preferred binding site.
• Computational modeling provides valuable insights into the complex interactions between platinum drugs and amino acids, aiding in drug design and understanding resistance mechanisms.